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This page was last updated 21/7/2002.
This site is about history, not current practice - my own prejudices about what in the history of insulin constitutes 'a Good Thing' (a la 1066 and All That) should not be taken as medical advice. I'm not a doctor my prejudices come from my personal experience of using insulin as a type 1 diabetic.
Since there are many websites which chronicle the early days of insulin, I will not deal with this topic, just point you to the discovery of insulin and another page about Banting. The Canadian Broadcasting Corporation has put some a film about the discovery
Not having broadband, I haven't seen it myself. Guidance for parents/viewers from someone who has: This film includes images of children/people before receiving insulin treatment and some viewers may find these images distressing.
The earliest insulin preparations manufactured in Toronto were soon commercially prepared by Eli Lilly in Indiana. Lilly held a monopoly on the preparation of insulin [I've been told that another company was manufacturing at the same time, but no details]. The early insulin was impure. The first patients had to endure injections of 5-10 ml intramuscularly. Pain and abscesses were common. As it became evident that this was going to be a life-long treatment, that it could be a means of more than extending life by a few weeks or months, it was recognised that injections had to be made more acceptable. Purity greatly improved and the volume of injections could be reduced to 1 ml or less in most cases (at this time insulin was prepared at 40 units per ml - compared to the standard today of 100 units per ml). But despite these refinements, there were still local reactions in some patients, especially in the early weeks.
The first type of insulin was quick- and short-acting ('soluble' or 'regular' insulin). Other names for this include 'R' and 'Actrapid'. It had to be injected at least twice daily - many patients were stabilized on four injections a day - before breakfast, lunch, dinner and bed.
At the time of insulin's discovery, August Krogh of Denmark, was in the USA at the time to talk about his work on capillaries - he was a Nobel Prize winner for his research. When he found that everyone he met talked of nothing but insulin, so he went to Toronto. When he returned to Denmark with H.C. Hagedorn he laid the foundation of the great Danish insulin manufacturing industry. They founded the Nordisk Insulinlaboratorium in 1923. The Nordisk Insulin Company was a non-profit-making concern which, together with the Novo Company, was responsible for making Denmark the main insulin-producing country outside the USA. Novo Terapeutisk Laboratorium was founded two years later.
Since 'regular' insulin had an activity curve of under 8 hours for most diabetics, with a peak at 2 - 4 hours, there was an obvious clinical need for a longer-acting preparation which could be injected before sleeping, and not have such a strong 'peak' - in this wise, it would not cause early-night low blood glucose episodes, and be better matched to the 'dawn phenomenon' experienced by a third or so of diabetics (and non diabetics) where the body dumps glucose into the blood in the late night (for non-diabetics, this engenders a corresponding rise in insulin levels, but diabetics experience a rise in blood glucose levels. In 1936 protamine zinc insulin was introduced. - it uses the protaphane or protamine polypeptide to delay and prologue the insulin activity curve. At Nordisk, Hagedorn developed Isophane insulin (Neutral Protamine Hagedorn - or NPH) in 1946 (Other names include Insulatard). This is a neutral insulin with prolonged action. Unlike the early protamine insulin, it could be mixed with Regular, and the activity curves of both Regular and NPH would remain identical - with a mix of Regular and Protamine, the curves would move together. For some diabetics, the 'blunting' effect of R+Protamine was a benefit, but for most, the ability to inject a mix of R+NPH, before breakfast and before dinner, was more convenient, and fitted their blood glucose curves better.
Following the introduction of NPH, a research team was gathered together at Novo with the aim of developing a similar insulin product that would be just as effective, and perhaps even better.. The research team achieved its aim. In 1953 Novo was able to present the Lente insulins - Ultralente, Lente and Semilente. For many years, a third of the world's insulin consumption was Lente family. Because the delaying agent was Zinc, to the benefits of a time-delayed insulin, there was the added benefit to patients of fewer allergic reactions. However, unlike NPH, Lente could not be mixed with R. While Lente had an activity curve similar to protamine zinc/NPH, Semilente had an action between that of R and NPH, while Ultralente had an action much longer. The three Lente insulins, plus Regular gave doctors and patients great flexibility in choosing a regime which exactly matched the diabetic's needs.
Since many doctors were prescribing regimes of fixed numbers of units of Regular and of NPH it was natural that pre-mixed insulins were marketed. The commonest waere a 50/50 blend of the two insulins, and a blend of 30% short acting, 70% long-acting (called 30/70 in some places, and 70/30 in others).
I have put a table at the end, which shows some trade names, and what they are composed of.
Impurities in insulin preparations were, in most cases, due to other pancreatic peptides which were present in tiny concentrations. In 1973, Novo produced a purer type of insulin, 'monocomponent' insulin (MC) insulin was introduced by Novo. This set a new standard in purity.
In 1982, Human Monocomponent was launched by Novo in 1982, this was the world's first insulin preparation identical to human insulin. It was pig insulin, modified by enzimes so that it was identical to human insulin.
When Novo tried to introduce monocompent insulin into the USA, Lilly fought back with 'human' Humulin insulins.
Before Human Monocomponent and Humulin insulins, insulin had been produced from animal sources, mainly cattle in the USA and the UK, pigs in Denmark. It is believed by some that the animal insulins provide the diabetic with better awareness of hypos, and it is certainly true that the long-acting animal insulins such as Ultralente are longer-acting than their 'human' equivalents. However, the fact that both pig and cattle differ from human insulin by one - three amino acids has lead the majority of physicians to recommend 'human' insulins. 'Animal' insulins are increasingly hard to find, particularly in the USA.
In response to Lilly, in 1987 Novo started production of so-called human insulin, using genetically engineered yeast cells.
In 1989 Novo Industri A/S and Nordisk Gentofte A/S merged, and thereby moved ahead of Lilly to become the world's leading producer of insulin.
In the late 1990s Lilly developed Lispro or Lyspro (also spelled lispro, and tradenamed Humalog). This was approved for prescription in the UK in June 1996 (available later in the US). This insulin has a shorter activity curve than Regular. This means it can be injected closer to the meal time, even after it. Studies have shown that it does not improve control as measured by long-term indicators (Hba1c), but that it does decrease the number of hypos. Unlike R, it cannot be mixed with NPH: if this is done, the action of the H is modified so that it is closer to R (this can, of course, be of benefit to some patients). However, it can be mixed with L without any effect.
Approved in the UK in 2002, this insulin (tradenamed Lantus) is being widely touted as better than other long-acting insulins because it has a _very_ flat action curve (like Ultralente), but, unlike U, it has only a 24 action. Some people find it acts a little shorter (and some doctors don't believe that's possible!!!!). Some doctors are prescribing it, in preference to pumps, to diabetics with marked dawn effect, or other known daily basal insulin requirement variation. Criminal, or at least unethical, in my view.
Apologies ... this history needs updating! At least two more short-acting and two more long-acting insulins have come to market since I last had time for a major update (2002).
Over the past few years, various manufacturers have started to cease production of many of the insulins listed here, much to the annoyance of those who found them ideally suited for managing their diabetes. Particularly unhelpful has been the withdrawal of animal insulins.
I am planning to refine this table, to indicate the source of the insulin, the tradename owner, and the date(s) at which the insulin was/is used.
| Generic name | Trade names* |
| Regular (R) | Actrapid, Velosulin. Humalin S, Pur-In Neutral |
| Isophane insulin Neutral Protamine Hagedorn - or NPH | Insulatard, Insulatard ge, Protophane, Hypurin Isophane, Pur-In Isophane, Humalin I (prb), Humalin I |
| Semilente | Semitard |
| (animal) Lente | Monotard (almost - Humulin Lente is actually a mix - see below), Hypurin Lente, Lentard |
| Ultralente | Ultratard, Humulin Zn, Hypurin Protamine Zinc |
*Note: the different trade names often indicate source - e.g. from pig, cattle, pig modified to 'human', or yeast. They can, therefore, have different actions in the individual.
| Name | is a blend of |
| Human Actraphane (pyr) | 70% NPH, 30% R |
| Human Initard 50/50 (emp) - | 50% NPH, 50% R |
| Human Mixtard (emp) | 70% NPH, 30% R |
| Humulin Lente (prb) | 70% Ultralente, 30% R |
| Humulin M1 | 90% NPH, 10% R |
| Humulin M2 | 80% NPH, 20% R |
| Humulin M3 | 70% NPH, 30% R |
| Humulin M4 | 60% NPH, 40% R |
| Pur-In Mix | 85% NPH, 15% R |
| Pur-In Mix 25/75 | 75% NPH, 25% R |
| Pur-In Mix 50/50 | 50% NPH, 50% R |
| Rapitard | ?% NPH, ?% R (please let me know, if you know) |
| Caninsulin | 30 % Semilente 70% Ultralente in a U 40 strength especially for animals! |
Again, two blends may appear to be identical insulins, but because their components have different sources, they can have different effects.
Blends: a note ... in the US, the proportion of blends are expressed as short acting first, long-acting second, and in the UK it is the other way round.